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AJP: Endocrinology and Metabolism
Year: 2010  |  Volume: 299  |  Issue: 2  |  Page No.: 145 - 161

PGC-1{alpha} regulation by exercise training and its influences on muscle function and insulin sensitivity

V. A Lira, C. R Benton, Z Yan and A. Bonen    


The peroxisome proliferator-activated receptor- (PPAR) coactivator-1 (PGC-1) is a major regulator of exercise-induced phenotypic adaptation and substrate utilization. We provide an overview of 1) the role of PGC-1 in exercise-mediated muscle adaptation and 2) the possible insulin-sensitizing role of PGC-1. To these ends, the following questions are addressed. 1) How is PGC-1 regulated, 2) what adaptations are indeed dependent on PGC-1 action, 3) is PGC-1 altered in insulin resistance, and 4) are PGC-1-knockout and -transgenic mice suitable models for examining therapeutic potential of this coactivator? In skeletal muscle, an orchestrated signaling network, including Ca2+-dependent pathways, reactive oxygen species (ROS), nitric oxide (NO), AMP-dependent protein kinase (AMPK), and p38 MAPK, is involved in the control of contractile protein expression, angiogenesis, mitochondrial biogenesis, and other adaptations. However, the p38 MAPK/PGC-1 regulatory axis has been confirmed to be required for exercise-induced angiogenesis and mitochondrial biogenesis but not for fiber type transformation. With respect to a potential insulin-sensitizing role of PGC-1, human studies on type 2 diabetes suggest that PGC-1 and its target genes are only modestly downregulated (≤34%). However, studies in PGC-1-knockout or PGC-1-transgenic mice have provided unexpected anomalies, which appear to suggest that PGC-1 does not have an insulin-sensitizing role. In contrast, a modest (~25%) upregulation of PGC-1, within physiological limits, does improve mitochondrial biogenesis, fatty acid oxidation, and insulin sensitivity in healthy and insulin-resistant skeletal muscle. Taken altogether, there is substantial evidence that the p38 MAPK-PGC-1 regulatory axis is critical for exercise-induced metabolic adaptations in skeletal muscle, and strategies that upregulate PGC-1, within physiological limits, have revealed its insulin-sensitizing effects.

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